Sudden cardiac death caused by ventricular tachyarrhythmia claims hundreds of thousands of victims each year. The proposed research will focus on the mechanisms that underlie such arrhythmias at their onset. This project will study two settings in which arrhythmias commonly occur: (1) acute regional ischemia caused by the sudden occlusion of a coronary artery and (2) nonischemic heart failure. The project will focus on mechanisms that involve the macro and microscopic anatomy of the heart and interactions between electrical and mechanical function. The broad long-range goal is to clarify events at the onset of ventricular arrhythmias and to suggest novel therapeutic strategies for preventing sudden death. There are three specific aims: Specific Aim 1. During acute regional ischemia, determine the relationship between mechanical stretch in the ischemic border zone and premature ventricular beats. The broad hypothesis of this aim is that premature ventricular beats during acute regional ischemia arise from highly stretched tissue along the border of the ischemic zone. The hypothesis will be tested using a novel optical method for simultaneously imaging electrical and mechanical function in whole isolated hearts. If the hypothesis is validated, it may suggest new therapeutic targets to suppress arrhythmia initiation. Specific Aim 2. Determine the role of the insertions of the right ventricle in the transition from electrically induced ventricular tachycardia to ventricular fibrillation in failing hearts. Sudden death in hear failure patients frequently begins with a rapid, yet organized, ventricular tachycardia that soon breaks down into ventricular fibrillation. The broad hypothesis of this aim is that the breakdown is most likely to occur where the right ventricle inserts into the septum, possibly because of the complex microanatomy of this region. The hypothesis will be tested in isolated swine hearts in which heart failure has been induced with rapid pacing. The main experimental tools will be panoramic optical imaging of membrane potential and diffusion tensor imaging of cardiac microstructure. We will also test interventions that attempt to prevent the onset of ventricular fibrillation by sup- pressing or delaying propagation block in this region. Specific Aim 3. Determine the role of the right ventricular insertions in the reinitiation of VF following failed shocks near the defibrillation threshold in failing hearts. The first postshock activations followig a shock near the defibrillation threshold typically emanate from a rapid focus. Sometimes these activations subside, allowing the resumption of sinus rhythm, but sometimes wavebreak occurs first, starting a cascade of further wavebreak events that sends the heart back into VF. The studies of Aim 3 will parallel those of Aim 2, but will focus on the mechanisms of the breakdown of post shock focal wavefronts at the right ventricular insertions. Many patients with nonischemic heart failure are now receiving implantable defibrillators for primary prevention of sudden death, highlighting the importance of improved understanding of defibrillation failure in this setting.